Ghrelin is a 28 amino acid peptide predominantly produced by the stomach and to a lesser extent by the bowel, pancreas, kidney, placenta, pituitary and the arcuate nucleus of the hypothalamus. It has only recently been purified and isolated from the rat and human stomach (Kojima et al., Nature 1999; 402: 656), where it has been found in X/A endocrine cells associated with the acid-secreting parietal cells of the gastric glands. Studies have shown that ghrelin acts on growth hormone secretagogue receptors (GHS-R), stimulates the release of growth hormone, induces rat adiposity (Tschöp et al., Nature 2000, 407(6806), 908), controls gastric acid secretion (Masuda et al., Biochemical and Biophysical Research Communications 2000; 276: 905) and when released within the rodent arcuate nucleus (Kojima et al., Nature 1999; 402: 656; Lu et al., Neuroscience Letters. 2002; 321(3):157) or when administered i.c.v. (Nakazato et al., Nature 2001; 409: 194; Shintani et al., Diabetes 2001;50: 227) stimulates an increase in food consumption. Systemically-administered ghrelin may also achieve the same, possibly by changing vagal nerve input to the brainstem vagal nuclei and hence, to the arcuate nucleus (Date et al., Gastroenterology 2002; 123: 1120). These studies indicate that GHS-R agonists have therapeutic utility in the treatment of different forms of cachexia and eating disorders.
Agonists of the ghrelin receptor have been described as useful in treating a growth hormone deficient state, stimulating an increase in food consumption thereby facilitating weight gain or maintenance of weight or appetite increase. This is particularly useful for a patient having a disease or disorder, or under going a treatment, that is accompanied by weight loss. Examples of diseases or disorders accompanied by weight loss include eating disorders (including anorexia, bulimia) cancer cachexia, AIDS, wasting, cachexia, and wasting in frail elderly. Examples of treatments accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, and dialysis.
Further work with growth hormone secretagogues [e.g., WO 97/24369] suggests roles for ghrelin receptor agonists in the treatment or prevention of frailty associated with ageing, the acceleration of the repair of fractured bone, reducing protein catabolism after major surgery or during chronic illness, improving muscle strength and mobility control of congestive heart failure, and other metabolic disorders. Studies with such compounds also indicate a role in the promotion of sleep quality [WO 97/24369], and in the improvement of congestive heart failure after administration of ghrelin (Nagaya et al., J. Clin. Endocrinol. Metab. 2001, 86, 5854-5859; Circulation 2001, 104, 1430-1435).
In both anaesthetized and conscious rodents and in conscious dogs, ghrelin increases gastric motility and emptying (anaesthetized rat motility Masuda et al., Biochemical and Biophysical Research Communications 2000; 276: 905; rat gastric emptying Trudel et al., American Journal of Physiology 2002; 282: G948; mouse gastric emptying Asakawa et al., Gastroenterology 2001; 120: 337). This action can also be illustrated in vitro, by showing an ability of rat ghrelin to facilitate electrically-evoked, excitatory nerve-mediated contractions in rodent gastric fundus strips, a response mimicked by partial 5-HT4 receptor agonists and indicative of a “prokinetic-like” response (Murray et al., British Journal of Pharmacology 2002; 136: 18P). Further, in conscious rats, i.c.v. administration of ghrelin reduces gastric acid secretion (Sibilia et al, Neuroendocrinology 2002; 75: 92); s.c. administration was without effect. Trudel and colleagues (American Journal of Physiology 2002; 282: G948) showed that ghrelin could reverse the gastric stasis created by invoking paralytic ileus via intestinal manipulation. Together, all of these data indicate that ghrelin might act as a gut hormone to facilitate both nutritional intake and digestion. This concurs with the proposal that the ability of ghrelin to evoke small reductions in pancreatic insulin secretion is consistent with the release of ghrelin during fasting conditions, when it will be important to maintain appropriate levels of blood sugars (see Muccioli et al., Eur J Pharmacology 2002, 440: 235).
Thus, in addition to conditions associated with cachexia (e.g. as a result of cancer), sarcopenia and/or those chronic diseases that may be exacerbated by loss of muscle mass (e.g. osteoporosis, rheumatoid arthritis, osteoarthritis, advancing age), growth hormone deficiency (e.g., when associated with age-related conditions), other disorders of metabolism, disorders in patterns of sleep or of congestive heart failure, GHS-R agonists will be useful treatments to alleviate symptoms associated with gastro-esophageal reflux and/or with dyspepsia, with or without appetite-/metabolic-related cachexia. Examples of such conditions include the reduction in feeding and the gastric stasis and emesis associated with anti-cancer treatment and other treatments or conditions which evoke similar symptoms, the gastroparesis associated with diabetes and gastroparesis and the symptoms associated with functional dyspepsia and gastro-esophageal reflux disease. Further, an ability to stimulate intestinal motility suggests that compounds active at ghrelin receptors will be useful treatments of paralytic ileus or pseudo-obstruction, and of conditions associated with constipation, such as constipation-predominant irritable bowel syndrome.
European patent application EP1159964 claims the use of compounds which stimulate the release of growth hormone as a means of stimulating the motility of the gastrointestinal system in a patient.
WO 95/06637 discloses a series of piperazine derivatives which are said to possess 5-HT1D receptor antagonist activity. WO0236562, WO132660, WO0005225, WO9942465 and WO9827081 all disclose arylpiperazine sulfonamide derivatives that are claimed to be 5-HT6 receptor antagonists. WO0274764, WO0274768, and WO0123374 all disclose dimethylpiperazine derivatives that are claimed to be selective 5HT1B receptor antagonists.